Process for producing substituted pyrroles

ABSTRACT

Alkyl 1,4-dialkylpyrrole-2-alkanoates are prepared by the selective decarboxylation of a 1,4-dialkyl-3-carboxypyrrole-2-alkanoic acid or an alkyl ester or alkali metal salt thereof under moderate conditions with a mixture of a strong mineral acid, an alkanol, and water. The products are useful for the preparation of anti-inflammatory agents.

CROSS-REFERENCE

This application is a continuation-in-part of copending application Ser.No. 209,950, filed Nov. 24, 1980, which in turn is acontinuation-in-part of application Ser. No. 203,052, filed Nov. 3,1980, both of which are now abandoned.

TECHNICAL FIELD

This invention relates to alkyl 1,4-dialkylpyrrole-2-alkanoates andderivatives thereof--more particularly to processes for preparing suchesters and derivatives.

BACKGROUND

As shown in Carson's U.S. Pat. No. 3,752,826 and its divisions, U.S.Pat. Nos. 3,865,840 and 3,952,012, it is known that alkyl1,4-dialkylpyrrole-2-alkanoates are desirable intermediates for thepreparation of 5-aroylpyrrole alkanoic acids, salts, esters, nitriles,amides, and substituted amides having anti-inflammatory activity.However, a disadvantage of employing them as intermediates in the pasthas been the lack of a simple, economical method of making them.

The simplest of Carson's processes for preparing alkyl1,4-dialkylpyrrole-2-alkanoates--the process taught in column 8 of U.S.Pat. No. 3,752,826--involves (1) hydrolyzing an alkyl1,4-dialkyl-3-alkoxycarbonylpyrrole-2-alkanoate under alkalineconditions, (2) partially re-esterifying the resultant diacid to analkyl 1,4-dialkyl-3-carboxypyrrole-2-alkanoate with an acidic solutionof a lower alkanol, and (3) decarboxylating the 3-position of theresultant partial ester by heating it in an inert atmosphere until gasevolution ceases or by heating it in a suitable basic solvent, such asquinoline. When a 5-aroyl derivative is desired, the product of thedecarboxylation step may be acylated with an appropriate aroyl halideunder Friedel-Crafts reaction conditions, or, alternatively, the aroylsubstitutent may be introduced prior to the hydrolysis step by thereactions taught by Carson in column 7.

As demonstrated in Carson's examples, specifically Examples LXXIII-LXXV,XCVIII-C, CIII-CV, CXIII-CXV, and CXXIII-CXXV, his alkyl1,4-dialkylpyrrole-2-alkanoate syntheses are multi-step, multi-potreactions requiring recovery of an intermediate product after each step,except when his partial esters are his starting materials. Suchprocesses are disadvantageous, of course, because of the cost andinconvenience inherent in processes requiring more than one step andmore than one reaction vessel--processes which (A) require more handlingsteps with attendant losses of increasingly valuable intermediates, (B)decrease positive process control, (C) increase opportunities for theintroduction of impurities, (D) increase waste stream handling, (E)increase processing costs for utilities to move large amounts ofintermediate materials from one reactor to another, and (F) can lead toa decrease in yield.

Moreover, even those Carson processes wherein his partial esters are hisstarting materials are disadvantageous. Those processes--although theyhave the desirable feature of being one-step processes--have theundesirable features of requiring (A) the use of considerably elevatedreaction temperatures, e.g., the temperatures of 180° C. or higher thatare shown in the aforementioned examples, and (B) the limitation of thestarting materials to alkyl 1,4-dialkyl-3-carboxypyrrole-2-alkanoates,which, having to be synthesized from the corresponding diesters anddiacids, are more expensive than the diesters and diacids that it wouldbe desirable to be able to employ in a one-step process for preparingalkyl 1,4-dialkylpyrrole-2-alkanoates.

It is known, of course, that Carson's decarboxylation technique, i.e.,heating a carboxylic material at a considerably elevated temperatureunder neutral conditions, is not the only means of decarboxylating acarboxylic material. Other references, such as Jones et al., TheChemistry of Pyrroles, Academic Press (1977), pages 327 and 329-331,show that decarboxylation of carboxylic materials, including somepyrrole acids, can be conducted under acidic, alkaline, or neutralconditions and that temperatures as low as 150° C. may be effective insome instances. However, the art does not suggest how knowndecarboxylation techniques could be adapted to overcome thedisadvantages of Carson and make it possible to develop a genericprocess capable of producing alkyl 1,4-dialkylpyrrole-2-alkanoates fromalkyl 1,4-dialkyl-3-alkoxycarbonylpyrrole-2-alkanoates or thecorresponding diacids, dicarboxylic acid salts, ester-salts,acid-esters, or acid-salts in a single step under moderate conditions.

SUMMARY OF THE INVENTION

An object of the invention is to provide novel processes for preparingalkyl 1,4-dialkylpyrrole-2-alkanoates.

Another object is to provide such processes capable of producing alkyl1,4-dialkylpyrrole-2-alkanoates from alkyl1,4-dialkyl-3-alkoxycarbonylpyrrole-2-alkanoates or the correspondingdiacids, dicarboxylic acid salts, ester-salts, acid-esters, oracid-salts in a single step under moderate conditions.

A further object is to provide novel processes for preparing alkyl1,4-dialkylpyrrole-2-alkanoate derivatives, in which processes the alkyl1,4-dialkylpyrrole-2-alkanoates are synthesized from alkyl1,4-dialkyl-3-alkoxycarbonylpyrrole-2-alkanoates or the correspondingdiacids, dicarboxylic acid salts, ester-salts, acid-esters, oracid-salts in a single step under moderate conditions.

These and other objects are attained by (A) contacting one molarproportion of a 2,3-disubstituted pyrrole corresponding to the formula:##STR1## with a mixture of about 2-15 molar proportions of a strongmineral acid and amounts of an R₁ OH alkanol and water such as toprovide an acid/alkanol mol ratio of about 0.5-6/1 and an acid/water molratio of about 0.3-10/1 at a temperature of about 40°-100° C. so as toform a pyrrole monoester corresponding to the formula: ##STR2## in whichformulas n is an integer of 1-6; R, R', R₁, and R₂ are independentlyselected from lower alkyl groups; T is hydrogen or an aroyl group; and Xand Z are independently selected from --COOH, --COOR₃, and --COOM,wherein R₃ is a lower alkyl group and M is sodium or potassium, and (B)when appropriate, converting the pyrrole monoester to a desiredderivative thereof.

DETAILED DESCRIPTION

The 2,3-disubstituted pyrrole employed as a starting material in thepractice of the invention may be a pyrrole diester resulting from thering-formation step in a process for producing 5-aroylpyrrole alkanoicacids, or it may be any suitable pyrrole having a carboxylic acid, alkylcarboxylate, and/or alkali metal carboxylate group substituted at the 2-and 3-positions, such as an appropriately substituted alkyl3-alkoxycarbonylpyrrole-2-alkanoate, alkyl 3-carboxypyrrole-2-alkanoate,3-carboxypyrrole-2-anoic acid, 3-alkoxycarbonylpyrrole-2-alkanoic acid,3-carboxypyrrole-2-alkanoic acid alkali metal salt,3-alkoxycarbonylpyrrole-2-alkanoic acid alkali metal salt,3-carboxypyrrole-2-alkanoic acid dialkali metal salt, etc. The compoundsin which X and Z of the formula are identical, i.e., are both --COOH,--COOR₃, or --COOM, are usually preferred, with the diesters being mostpreferred.

When at least one of the X and Z groups is --COOR₃, the esterifyinggroup may be any lower alkyl group--"lower alkyl" being used in thisspecification in its usual sense to denote an alkyl group containing 1-6carbons, e.g., methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl,etc. However, it is generally preferred that an esterifying group be analkyl group containing 1-4 carbons, most preferably ethyl.

As indicated by the formula, the carboxylic acid, ester, or salt groupat the 3-position is directly attached to the pyrrole ring, whereas thecorresponding group at the 2-position is attached to the ring through analkylene group containing 1-6, preferably 1-4, carbons. Thus, the2-substituent in the 2,3-disubstituted pyrrole may be an acetic,propionic, butyric, valeric, hexanoic, or heptanoic group; but it ispreferably an acetic group, i.e., a substituent wherein n of the formulais 1.

As also indicated by the formula, the 2,3-disubstituted pyrrole haslower alkyl substituents in the 1- and 4-positions and may have an aroylsubstituent in the 5-position. The lower alkyl substituents on thepyrrole ring may be the same or different, but they are preferably thesame and are most preferably methyl. The aroyl substituent, whenpresent, may be any of the aroyl substituents taught in the prior art on5-aroylpyrrole compounds having pharmaceutical application, i.e.,substituents in which the aryl group which is connected to the pyrrolering by a carbonyl carbon is a thienyl, 5-methylthienyl, phenyl, ormono- or polysubstituted phenyl group, any substituent on the phenylring being halo, lower alkyl or alkoxy, trifluoromethyl, nitro, amino,cyano, or methylthio. However, the preferred 2,3-disubstituted pyrroleshave no substituent in the 5-position. When it is desired to have a5-aroyl substituent in the final product, it may conveniently be addedafter formation of the pyrrole monoester to minimize the loss ofvaluable and expensive reagents.

The acid used in the practice of the invention is a strong mineral acid,e.g., sulfuric acid, phosphoric acid, perchloric acid, etc.--all that isrequired for utility being that the acid be capable of catalyzing thedesired reaction of the 2,3-disubstituted pyrrole without degrading thepyrrole monoester product. Since highly dilute acids react with anddegrade that product, the acid should be concentrated and is preferablyhighly concentrated. For example, concentrated sulfuric acid containing96% sulfuric acid, with the remainder being water, is particularlypreferred. The amount of acid employed is in the range of about 2-15,preferably about 3.75-10, mols per mol of 2,3-disubstituted pyrrole.

The alkanol of the reagent mixture can be any lower alkanol, e.g.,methanol, ethanol, propanol, isopropanol, butanol, pentanol, hexanol,etc.; but it is preferably one in which the alkyl group is the same asany esterifying alkyl group in the 2,3-disubstituted pyrrole. Thus, whenX or Z of the 2,3-disubstituted pyrrole formula is --COOR₃, it ispreferred that the alkanol be methanol when R₃ is methyl, propanol whenR₃ is propyl, etc. In the preferred embodiment of the invention whereinthe 2,3-disubstituted pyrrole contains ethyl ester groups, of course, itis preferred that the alkanol be ethanol.

Both the alkanol and the water of the reagent mixture are employed topermit the products to be obtained in suitable yields. However, asindicated above, the use of too much water leads to product degradationby dilute acid; and it has also been found that the use of too much ortoo little of either the water or the alkanol decreases the yield. It isnaturally desirable to employ each of the ingredients of the reagentmixture in an amount such as to minimize the amounts of reagentingredients employed, simplify processing, maintain high yields,decrease the amounts of impurities formed, and decrease reagentpurification, disposal, or recycle. The optimum concentration of eachingredient in the reaction mixture to achieve these ends can vary withthe concentrations of the other ingredients and with the nature of theparticular 2,3-disubstituted pyrrole being reacted. However, it has beenfound that desirable results are achieved when the ingredients of thereagent mixture are employed in amounts such as to provide an acid/watermol ratio in the range of about 0.3-10/1 and an acid/alkanol mol ratioin the range of about 0.5-6/1.

In the preferred embodiments of the invention wherein the2,3-disubstituted pyrrole is an alkyl 3-alkoxycarbonylpyrrole-2-acetateor 3-carboxypyrrole-2-acetic acid, it has been found preferable toemploy the ingredients of the reagent mixture in amounts such as toprovide acid/alkanol mol ratios in the range of about 1-5/1 and0.75-2/1, respectively, and acid/water mol ratios in the range of about2-5/1.

The process of the invention is conducted by contacting the2,3-disubstituted pyrrole with the reagent mixture and then heating thereaction mixture with agitation for a period sufficient to complete thereaction.

The manner of combining the 2,3-disubstituted pyrrole and theingredients of the reagent mixture is not critical. If desired, the2,3-disubstituted pyrrole may be dissolved in a suitable solvent, e.g.,methylene chloride, toluene, etc., prior to being contacted with thereagent mixture; but excellent results are also achieved when thereaction is conducted in the absence of a solvent. It is generallypreferred to add the reagent mixture to the 2,3-disubstituted pyrrole,but it may sometimes be desirable to add the 2,3-disubstituted pyrroleto the reagent mixture. Also, when the reagent mixture is added to the2,3-disubstituted pyrrole, the ingredients may be premixed or addedsequentially, e.g., by adding the alkanol and then aqueous acid or byadding the alkanol, then the acid, and then the water, etc.--the onlycriticality being that the ingredients be added in the amounts indicatedabove.

The rate of reaction generally increases with an increase intemperature, and the process of the invention can be conducted atelevated temperatures as long as the temperatures are not so high as todegrade the products. However, conventional decarboxylationtemperatures, e.g., about 200°-210° C., can affect the product adverselyand reduce the yields substantially, while lower temperatures in therange of about 40°-100° C., preferably about 60°-85° C., have been foundto be useful.

The time required for the reaction varies with the temperature employedand is not a critical variable. A small-scale reaction can be completedin less than an hour at a temperature of about 80° C., and the reactiontime has varied from about 5-24 hours at 60° C. in larger-scalereactions without having any substantial adverse effect on yields.

When the reaction has been completed, the product can be recovered byextraction into an organic phase. The extraction should be conducted soas to minimize handling losses and the production of degradationby-products and, in a preferred embodiment of the invention, isconducted by (1) cooling the reaction mixture, (2) adding an organicsolvent in which the pyrrole monoester is more soluble than in diluteacid, and (3) diluting with cold water while using vigorous agitation.Maintenance of a relatively low temperature during dissolution orextraction minimizes product losses from degradation of the product withthe dilute acid that must be formed to permit extraction of the productwith the organic solvent because of the high solubility of the pyrrolemonoesters in the concentrated acid.

The solvent used for the extraction of the product can be any organicsolvent in which the pyrrole monoester is more soluble than in thedilute acid. However, it is generally a chlorinated hydrocarbon oraromatic hydrocarbon, such as methylene chloride, carbon tetrachloride,chloroform, dichloroethane, benzene, toluene, xylene, monochlorobenzene,etc. When the product is to be converted to a derivative, such as a5-aroylpyrrole anti-inflammatory agent, in a solvent, unnecessarysolvent recovery and purification steps can be avoided by using as theextracting solvent a solvent that will also be useful in the subsequentreaction. Thus, toluene is a particularly preferred extractant when ananti-inflammatory agent is to be prepared from the pyrrole monoester.

When derivatives of the pyrrole monoesters, e.g.,1,4-dialkyl-5-aroylpyrrole-2-alkanoic acids, salts, amides, etc., aredesired, they may be prepared by employing conventional techniques,e.g., conventional acylation, hydrolysis, ammonolysis, etc., techniquesto convert the products of the present process to the desiredderivatives. The particular conventional techniques used to convert thepyrrole monoesters into their various derivatives are not critical. Itmay sometimes be desirable to use certain particular techniques for thepreparation of the derivatives, e.g., the acylation, hydrolysis, andammonolysis techniques taught in the aforementioned Carson references,the disclosures of which are incorporated herein by reference. However,the overall processes for preparing the derivatives are simplified andmade more efficient and economical by the present simplification of thesynthesis of the pyrrole monoesters, regardless of the particulartechniques used to convert them into their various derivatives.

The following examples are given to illustrate the invention and are notintended as a limitation thereof. In these examples certainabbreviations are used as defined below:

    ______________________________________                                        Abbreviation  Definition                                                      ______________________________________                                        EtOH          Ethanol                                                         PAT           Ethyl 1,4-dimethylpyrrole-2-acetate                             PDE           Ethyl 1,4-dimethyl-3-ethoxycarbon-                                            ylpyrrole-2-acetate                                             TMP           1,2,4-Trimethylpyrrole                                          TMPE          1,2,4-Trimethyl-3-ethoxycarbonyl-                                             pyrrole                                                         nd            none detected                                                   % Yield       Yield determined by gas chromato-                                             graphy using an internal standard                               % Yield*      Yield based on weight of product                                              isolated after distillation                                     ______________________________________                                    

EXAMPLE 1

To 50 grams of a solution of 20% ethyl1,4-dimethyl-3-ethoxycarbonylpyrrole-2-acetate (10 grams, 40 mmoles) intoluene containing 2.4 ml of absolute ethanol (1.9 grams, 41 mmoles)were added, dropwise, over 20 minutes, 8.6 ml of 96% sulfuric acid (15grams, 160 mmoles, containing 0.63 gram, 35 mmoles of water). During theaddition, the temperature of the reaction mixture rose to about 50° C.,and the mixture became heterogeneous. The reaction mixture was thenheated in an oil bath at 75°-80° C. for 75 minutes with stirring. Gasevolution was observed. The reaction mixture was then diluted with 25 mlof toluene and cooled to 5° C. Then 75 ml of ice water was added in oneportion with vigorous stirring. After five minutes, the organic layerwas separated and dried with magnesium sulfate. Gas chromatographicanalysis indicates the toluene contained 9% ethyl 1,4-dimethylpyrrole-2-acetate. The toluene was removed by vacuum distillation at 100 mm ofmercury followed by vacuum distillation of the residue at 1 mm ofmercury to give a fraction which weighed 5.5 grams. This corresponds toa 78% yield of ethyl 1,4-dimethylpyrrole-2-acetate.

Gas chromatographic analysis employed a Hewlett-Packard Model 5830Ainstrument using a 10 foot, 1/8 inch column packed with 10% DEGS onChromosorb Q. Dibutyl phthalate was used as an internal standard and wasadded to the sample after work-up to avoid decomposition in the strongacid.

EXAMPLES 2-8

The purpose of this series of experiments is to illustrate therequirement for each of the components in the reagent mixture and toestablish relative ratios of sulfuric acid, ethanol and water. To anumber of 100 mg samples of ethyl1,4-dimethyl-3-ethoxycarbonylpyrrole-2-acetate was added a variety ofdifferent solutions. The resultant mixtures were heated for about 18hours at 65°-66° C. followed by pouring into 10 ml of water andextracting three times with 10 ml of methylene chloride. Each organicsolution was dried with magnesium sulfate and the solvent was removed invacuo. The residues were then heated at 190°-200° C. for 20 minutes toassure that they were entirely decarboxylated. Since all samples weretreated in the same manner and the only variation was with respect tothe reagent mixture added, the examples illustrate the relativeimportance of the components in that mixture. The composition of thereagent mixture and the results obtained as percent yield ofby-products, starting materials and desired ethyl1,4-dimethylpyrrole-2-acetate are given in the following Table 1.

                  TABLE 1                                                         ______________________________________                                        Reagent Mixture Composition Variability Study                                        Reagent Composition                                                    Example                                                                              H.sub.2 SO.sub.4 /EtOH/H.sub.2 O                                                             % Yield                                                 No.    (Molar Ratio)  By-Products                                                                              PAT  PDE                                     ______________________________________                                        2      1/0/0.22       21          3   <1                                      3      1/0.17/0.22    15          8   16                                      4      1/0/0.77       13          7    2                                      5      1/4.8/16       26         nd   38                                      6      1/1.9/6.4      18         19   25                                      7      1/0.47/1.8      9         48   nd                                      8      1/0.24/0.50    15         26   13                                      ______________________________________                                    

Note that the absence of ethanol and the low amount of water in Examples2 and 4 and the low amount of ethanol in Example 3 provide very lowyields of the desired product. In contrast, when both ethanol and waterare included in sufficient relative proportions as in Example 7, theyield of desired product is much higher. Further, Examples 2-8 show thatthe relative ratio of acid/ethanol/water is important since, if too muchethanol and water are present, the yield is substantially lower or noreaction occurs. However, as the ratio of acid to both ethanol and waterincreases, the yield of desired product reaches a maximum and thenbegins to decrease as the amount of acid exceeds by a large amount therelative amounts of ethanol and water. Note Examples 5 to 8,particularly. Therefore, the above results indicate that acid, alkanoland water are all required and that the relative proportions of each ofthe reagents are of great significance.

EXAMPLES 9-10

The effects of temperature and time were determined for a specifiedreagent mixture of sulfuric acid, ethanol and water at a molar ratio of1/0.47/1.8, respectively, in the following Examples 9-10. Two constanttemperature runs were made in which 0.5 gram of ethyl1,4-dimethyl-3-ethoxycarbonylpyrrole-2-acetate was put into 6.7 grams(about 5 ml) of a solution consisting of 96% sulfuric acid, water, andabsolute ethanol in a volume ratio of 2/1/1. The reaction mixture washeated at 60° C. in Example 9 and at 80° C. in Example 10 under a watercondenser. Every hour, 1/2 ml of reaction mixture was worked up bypouring into 5 ml of water and extracting three times with 5 ml portionsof methylene chloride. The organic layers were dried with magnesiumsulfate and stripped, and the resultant residue was analyzed by gaschromatography using dibutyl phthalate as an internal standard. Theresults of the two examples are shown in Table 2 below.

                  TABLE 2                                                         ______________________________________                                        Effect of Temperature and Time on Preparation of                              Ethyl 1,4-Dimethylpyrrole-2-Acetate                                           Example Reaction    Percent Yield                                             No.     Time (hr)   TMP    PAT    TMPE  PDE                                   ______________________________________                                        Part A                                                                         9      1           10     27     9     30                                            2           18     48     3     15                                            3           22     59     1      7                                            4           23     62     1      3                                            6           26     65     nd    nd                                            24          24     67     nd    nd                                    Part B                                                                        10      1           28     61     nd    nd                                            2           30     57     nd    nd                                            3           30     58     nd    nd                                            4           33     57     nd    nd                                            5           29     48     nd    nd                                            6           37     47     nd    nd                                            72          26     28     nd    nd                                    ______________________________________                                    

From the table, it can be seen that the reaction time and temperatureare not as critical as the reagent composition. Similar yields of thedesired product, ethyl 1,4-dimethylpyrrole-2-acetate, were obtainedafter 3 or 4 hours at 60° C. or after 1 hour at 80°.

EXAMPLES 11-24

The following series of examples illustrates the effect of varying thepyrrole diester-treating reagent composition by using different relativeamounts of acid, lower alkanol, and water. The effect on the yield ofthe pyrrole monoester is clearly shown.

In each example, one part by weight of ethyl1,4-dimethyl-3-ethoxycarbonylpyrrole-2-acetate was heated with about10.5-18.6 parts by weight of a reagent solution for one hour at atemperature of 76°-84° C. in a suitable flask provided with a watercondenser and maintained in an oil bath. After the resultant reactionmixture was allowed to cool, it was poured into 10 ml of water andextracted three times with 10 ml portions of methylene chloride. Thecombined organic layers were dried with magnesium sulfate andconcentrated in vacuo, and the residue was subjected to gaschromatographic analysis using dibutyl phthalate as the internalstandard. The results of these runs are given below in Table 3.

                  TABLE 3                                                         ______________________________________                                        Preparation of Ethyl 1,4-Dimethylpyrrole-2-Acetate                            Using Variable Reagent Composition                                                   Composition                                                            Example                                                                              H.sub.2 SO.sub.4 /EtOH*/H.sub.2 O                                                            Percent Yield                                           No.    (Molar Ratio)  TMP    PAT  TMPE  PDE                                   ______________________________________                                        11     1/0.11/0.61    14      7   14    8                                     12     1/0.19/0.89    13     15   15    20                                    13     1/0.31/1.3     28     55    1    3                                     14     1/0.47/1.8     24     61   nd    1                                     15     1/0.72/2.6     22     66   nd    2                                     16     1/1.1/3.9       9     16   16    39                                    17     1/1.9/6.4       1      1   18    55                                    18     1/0.86/0.53    10     78   nd    2                                     19     1/0.75/0.83    15     74   nd    2                                     20     1/0.67/1.2     14     64   nd    1                                     21     1/0.58/1.5     17     49    3    1                                     22     1/0.39/2.1     26     48    1    7                                     23     1/0.28/2.4     39     47   nd    nd                                    24     1/0.19/2.7     46     40   nd    1                                     ______________________________________                                    

For the purposes of illustration, the strong acid employed in theprevious examples has been sulfuric acid. The following examplesillustrate the use of other strong acids which are illustrative of theinvention.

EXAMPLE 25

To 101 mg of ethyl 1,4-dimethyl-3-ethoxycarbonylpyrrole-2-acetate wasadded 1 ml of a 1/1 volume mixture of absolute ethanol and 86%phosphoric acid. The mixture was heated in an 80° C. oil bath for 1hour, poured into 10 ml of water, and extracted with three 10 mlportions of methylene chloride. The combined organic layers were dried(magnesium sulfate) and concentrated in vacuo to give a residue weighing67 mg. Gas chromatographic analysis of this residue indicated itcontained 33 mg (46%) of ethyl 1,4-dimethylpyrrole-2-acetate.

EXAMPLE 26

To 103 mg of ethyl 1,4-dimethyl-3-ethoxycarbonylpyrrole-2-acetate wasadded 1 ml of a solution of 1.5 ml of absolute ethanol in 5 ml of 70%perchloric acid. The mixture was heated in an 80° C. oil bath for 1hour, poured into 10 ml of water, and extracted with three 10 mlportions of methylene chloride. The combined organic layers were dried(magnesium sulfate) and concentrated in vacuo to give a residue weighing69 mg. Gas chromatographic analysis of this residue indicated itcontained 49 mg (66%) of ethyl 1,4-dimethylpyrrole-2-acetate.

The pyrrole monoester product can be prepared from the diester neat orin the presence of a solvent. Further, while the work-up is notcritical, it can have an effect on the yield of the product because ofdegradation of the pyrrole monoester product by dilute acid.Accordingly, the following examples illustrate preparation of theproduct pyrrole monoester in the presence of a solvent and show theresults of work-up under conditions which do not adversely affectproduct yields.

EXAMPLES 27-31

A toluene solution of one molar proportion of PDE was reacted with areagent mixture of 5 molar proportions of sulfuric acid, 1 molarproportion of ethanol, and 1.1 molar proportions of water at 80° C. for75 minutes. The reaction mixture was then cooled to room temperature,diluted with the amount of water indicated in Table 4, and extractedwith the indicated amount of toluene. The yields of PAT obtained arealso indicated in the table.

                  TABLE 4                                                         ______________________________________                                        Preparation of PAT                                                            Example Amt. of  Size of     No. of                                           No.     Water**  Extract***  Extracts                                                                             % Yield                                   ______________________________________                                        27      105      16          3      66                                        28      117      16          4      62                                        29      234      16          4      63                                        30      134      11          4       74*                                      ______________________________________                                         **Mols of diluting water/mol PDE                                              ***Mols of extracting solvent/mol PDE/extract                            

EXAMPLE 31

Example 27 was repeated except that the reaction mixture was dilutedwith 328 molar proportions of water and extracted with three 66 molarproportion aliquots of methylene chloride. The yield of PAT was 65%.

EXAMPLE 32

Example 31 was repeated except that neat PDE was employed instead of atoluene solution. The yield of PAT was 73%.

EXAMPLE 33

Example 28 was repeated except that neat PDE was employed instead of atoluene solution, and only three toluene extracts were made. The yieldof PAT was 63%.

EXAMPLE 34

One molar proportion of PDE, employed as a 63% melt, was reacted with areagent mixture of 5 molar proportions of sulfuric acid, one molarproportion of ethanol, and 1.1 molar proportions of water at 80° C. for75 minutes. The reaction mixture was then divided in half. Each half ofthe reaction mixture was cooled, diluted with 223 molar proportions ofwater, and extracted with four 19 molar proportion aliquots of toluene.However, the half of the reaction mixture employed in Part A was cooledto room temperature before being diluted, and the half in Part B wascooled to 5° C. The yield* of PAT was 66% in Part A and 67% in Part B.

EXAMPLE 35

Example 34, Part A, was repeated except that the 63% PDE melt wasemployed as a methylene chloride solution, and the extracting solventwas methylene chloride instead of toluene. The yield* of PAT was 73%.

EXAMPLE 36

One molar proportion of neat PDE was reacted with a reagent mixture of10 molar proportions of sulfuric acid, 10 molar proportions of ethanol,and 5 molar proportions of water at 80° C. for 75 minutes. The reactionmixture was then cooled to room temperature, diluted with 105 molarproportions of water, and extracted with four 20 molar proportionaliquots of methylene chloride. The yield* of PAT was 72%.

EXAMPLE 37

Example 36 was repeated except that the extracting solvent was tolueneinstead of methylene chloride. The yield of PAT was 67%.

EXAMPLE 38

Example 36 was repeated except that the reaction mixture was divided inhalf after dilution with water. One half was extracted with four 40molar proportion aliquots of methylene chloride (Part A) and the otherwith four 40 molar proportion aliquots of toluene (Part B). The yield ofPAT was 76% in Part A and 74% in Part B.

EXAMPLE 39

One molar proportion of neat PDE was reacted with a reagent mixture of10 molar proportions of sulfuric acid, 10 molar proportions of ethanol,and 5 molar proportions of water at 80° C. for 75 minutes. The reactionmixture was then cooled to room tempeature, diluted with 328 molarproportions of water, and extracted with three 66 molar proportionaliquots of methylene chloride. The yield of PAT was 76%.

EXAMPLE 40

Example 39 was repeated except that the amount of diluting water was 117molar proportions, and the extraction was made with four 16 molarproportion aliquots of toluene. The yield of PAT was 64%.

EXAMPLE 41

Example 39 was repeated except that the PDE was employed as a toluenesolution, the amount of diluting water was 84 molar proportions, and theextraction was made with five 5 molar proportion aliquots of toluene.The yield* was 54%.

EXAMPLE 42

One molar proportion of neat PDE was reacted with a reagent mixture of 9molar proportions of sulfuric acid, 0.65 molar proportion of ethanol,and 2 molar proportions of water at 80° C. for 75 minutes. The reactionmixture was then cooled to room temperature, diluted with 94 molarproportions of water, and extracted with three 16 molar proportionaliquots of toluene. The yield of PAT was 15%.

EXAMPLE 43

A toluene solution of one molar proportion of PDE was reacted with areagent mixture of 3.75 molar proportions of sulfuric acid, one molarproportion of ethanol, and 0.8 molar proportion of water at 80° C. for75 minutes. The reaction mixture was then cooled to room temperature,diluted with 134 molar proportions of water, and extracted with four 11molar proportion aliquots of toluene. The yield* of PAT was 67%.

EXAMPLE 44

Example 43 was repeated except that the reaction mixture was cooled to5° C., diluted with 100 molar proportions of water, and extracted withone 16 molar proportion aliquot of toluene. The yield* of PAT was 79%.

EXAMPLE 45

To 101.5 mg of ethyl 1,4-dimethyl-3-carboxypyrrole-2-acetate were added0.13 ml of ethanol and, dropwise, 0.13 ml of 96% sulfuric acid. Thereaction mixture was then heated at 80° C. for 1 hour and 15 minutes,cooled, and poured into 2 ml of water. The diluted reaction mixture wasthen immediately extracted three times with 5 ml portions of methylenechloride. The combined organic layers were dried over magnesium sulfate,and the methylene chloride was removed in vacuo to give 76.5 mg ofliquid. This was shown to contain, by gas chromatographic analysis usingan internal standard, 75% ethyl 1,4-dimethylpyrrole-2-acetate which is a70% yield.

EXAMPLE 46

To 99.8 mg of 1,4-dimethyl-3-ethoxycarbonylpyrrole-2-acetic acid wereadded 0.13 ml of ethanol and, dropwise, 0.13 ml of 96% sulfuric acid.The reaction mixture was then heated at 80° C. for 1 hour and 15minutes, cooled, and poured into 2 ml of water. The diluted reactionmixture was then immediately extracted three times with 5 ml portions ofmethylene chloride, and the methylene chloride was removed in vacuo togive 76.1 mg of a liquid. This was shown to contain, by gaschromatographic analysis using an internal standard, 72% ethyl1,4-dimethylpyrrole-2-acetate, which is a 68% yield.

EXAMPLE 47

To a mixture of 6.13 g (0.06 mole) of 96% H₂ SO₄ and 2.07 g (0.045 mole)of ethanol, cooled to room temperature, were added 3.69 g (0.015 mole)of 80% by weight 1,4-dimethyl-3-carboxypyrrole-2-acetic acid. Thisprovided an initial molar ratio of 1/4/0.5/3 of pyrrole reactant to acidto water to alkanol, respectively. The reaction mixture was heated withagitation at 70° C. for 3.5 hours. After 30 minutes of heating, 7.5 mlof toluene were added to aid agitation and decrease foaming caused bygas evolution. The reaction mixture was cooled to room temperature, 16 gtoluene were added, and then a solution of 2.40 g of NaOH (0.06 mole)and 10.8 g H₂ O was slowly added at ice bath temperatures. The reactionmixture was stirred for 30 minutes, after which the organic and aqueousphases were separated. Gas chromatographic analysis of the toluenesolution indicated 6.4% of ethyl 1,4-dimethylpyrrole-2-acetate, which isa 59% yield.

EXAMPLE 48

Following the procedure of Example 47, another experiment was carriedout in the same manner except that 3.46 g (0.075 mols) of ethanol wereemployed to give a molar ratio in the initial reaction mixture of1/4/0.5/5 of pyrrole reactant, acid, water, and alkanol, respectively.After the same heating procedure as above, followed by cooling to roomtemperature, toluene and caustic workup, and separation, there wasobtained 25 g of the organic phase, which by gas chromatographicanalysis, contained 6.6% ethyl 1,4-dimethylpyrrole-2-acetate, which is a62% yield.

EXAMPLE 49

The procedure of Examples 47 and 48 was varied by mixing all reactantsexcept the sulfuric acid and then adding it gradually over a period oftime. To an agitated mixture of 3.46 g (0.075 mole) of ethanol, 2.90 g(0.015 mole) of 1,4-dimethyl-3-carboxypyrrole-2-acetic acid, and 7.5 gof toluene were added 6.13 g (0.06 mole) of 96% sulfuric acid, dropwise,over a period of 30 minutes. The reaction mixture was heated at 70° C.for 2 hours and then cooled to room temperature. Then 16 g of toluenewere added, the reaction mixture was placed in an ice water coolingbath, and a solution of 2.4 g (0.06 mole) sodium hydroxide and 12.8 gwater was added over ten minutes. The resultant mixture was stirred for30 minutes and the organic phase, weighing 26.1 g, was separated. Basedon the gas chromatographic analysis, the yield of ethyl1,4-dimethylpyrrole-2-acetate was 80%.

EXAMPLE 50

The procedure of Example 49 was repeated except that the initialreactant mixture was heated in a 60° C. bath for 30 minutes followed byincreasing the bath temperature to 80° C. and heating for an additional1 hour and 40 minutes. Following workup, as previously described, therewas obtained 26.1 g of the organic layer, which is an 84% yield of ethyl1,4-dimethylpyrrole-2-acetate.

EXAMPLE 51

To a stirred mixture of 2.56 g (0.0117 mole) of1,4-dimethyl-3-carboxypyrrole-2-acetate monosodium salt and 2.7 g(0.0585 mole) of ethanol in 10 g of toluene at room temperature slowlywere added 4.78 g (0.0468 mole) of 96% sulfuric acid over a fifteenminute period. The initial molar ratio of pyrrole reactant to acid towater to alkanol was 1/4/0.9/5, respectively. The reaction mixture washeated for 30 minutes in a 60° C. bath and then for one hour and 15minutes in an 80° C. bath. The reaction mixture was then cooled to roomtemperature, and 8.3 g of toluene were added. The reaction mixture wasthen placed in an ice water bath, and a solution of 1.9 g of NaOH and8.5 g of water was slowly added. After stirring at room temperature forthirty minutes, another 2.1 g of water were added to dissolve solidswhich appeared. The phases were separated, and the organic phase weighed20.2 grams. Gas chromatographic analysis showed 7.34% ethyl1,4-dimethylpyrrole-2-acetate, which is a 70% yield. The analysis alsoshowed 1.8% of ethyl 1,4-dimethyl-3-ethoxycarbonylpyrrole-2-acetate,which is a 13% yield.

EXAMPLE 52

The procedure of Example 51 was followed, except that the pyrrolereactant was 2.3 g (0.0095 mole) of1,4-dimethyl-3-carboxypyrrole-2-acetic acid disodium salt. This wasmixed with 2.2 g (0.0478 mole) of ethanol and 14.9 g (0.0162 mole) oftoluene using stirring at room temperature. Then 5.85 g (0.0573 mole) of96% sulfuric acid were added. The molar ratio of pyrrole reactant toacid to water to alkanol was 1/6/1.3/5, respectively. After stirring for30 minutes upon completion of the mixing, the reaction mixture washeated in a 60° C. bath for 30 minutes and then placed in an 80° C. bathfor 2 hours. The reaction mixture was then cooled with an ice waterbath, and a solution of 1.55 g of NaOH and 6.9 g of water was slowlyadded over a fifteen minute period. The diluted reaction mixture wasstirred for 30 minutes while being brought to room temperature, and theorganic phase, weighing 26.4 g, was separated. Gas chromatographicanalysis shows the organic phase contained 8.7% of ethyl1,4-dimethyl-pyrrole-2-acetate and 0.64% of ethyl1,4-dimethyl-3-ethoxycarbonylpyrrole-2-acetate, which are yields of 83%and 4.4%, respectively.

This invention is susceptible to considerable variation within thespirit and scope of the appended claims.

I claim:
 1. A process which comprises contacting one molar proportion ofa 2,3-disubstituted pyrrole corresponding to the formula: ##STR3## witha mixture of about 2-15 molar proportions of a strong mineral acid andamounts of an R₁ OH alkanol and water such as to provide an acid/alkanolmol ratio of about 0.5-6/1 and an acid/water mol ratio of about 0.3-10/1at a temperature of about 40°-100° C., so as to form a pyrrole monoestercorresponding to the formula: ##STR4## in which formulas n is an integerof 1-6; R, R', R₁, and R₂ are independently selected from lower alkylgroups; T is hydrogen or an aroyl group; and X and Z are independentlyselected from --COOH, --COOR₃, and --COOM, wherein R₃ is a lower alkylgroup and M is sodium or potassium.
 2. The process of claim 1 whereinthe acid is sulfuric acid.
 3. The process of claim 1 wherein n is
 1. 4.The process of claim 1 wherein R and R' are methyl.
 5. The process ofclaim 1 wherein R₁ and R₂ are ethyl.
 6. The process of claim 1 wherein Tis hydrogen.
 7. The process of claim 1 wherein X and Z are --COOH. 8.The process of claim 1 wherein X and Z are --COOM.
 9. The process ofclaim 1 wherein X and Z are --COOR₃.
 10. The process of claim 9 whereinR₃ is ethyl.
 11. The process of claim 1 wherein the 2,3-disubstitutedpyrrole is dissolved in an organic solvent prior to being contacted withthe acid/alkanol/water mixture.
 12. The process of claim 1 wherein thecontacting is effected by adding the acid/alkanol/water mixture to the2,3-disubstituted pyrrole.
 13. The process of claim 1 wherein thepyrrole monoester is recovered by diluting the reaction mixture withwater, extracting the dilute solution with an organic solvent, anddistilling the pyrrole monoester from the solvent.
 14. The process ofclaim 13 wherein the solvent is methylene chloride.
 15. The process ofclaim 13 wherein the solvent is toluene.
 16. A process which comprisescontacting one molar proportion of an alkyl3-alkoxycarbonylpyrrole-2-acetate corresponding to the formula: ##STR5##with a mixture of about 2-15 molar proportions of a strong mineral acidand amounts of an R₁ OH alkanol and water such as to provide anacid/alkanol mol ratio of about 0.5-6/1 and an acid/water mol ratio ofabout 0.3-10/1 at a temperature of about 40°-100° C., so as to form apyrrole monoester corresponding to the formula: ##STR6## in which theformulas R, R', R₁, and R₃ are independently selected from lower alkylgroups.
 17. The process of claim 16 wherein the ingredients of thereaction mixture are employed in amounts such as to provide anacid/alkyl 3-alkoxycarbonylpyrrole-2-acetate mol ratio of about3.75-10/1, an acid/alkanol mol ratio of about 1-5/1, and an acid/watermol ratio of about 2-5/1.
 18. The process of claim 16 wherein the acidis sulfuric acid.
 19. The process of claim 16 wherein R and R' aremethyl.
 20. The process of claim 16 wherein R₁ and R₃ are ethyl.
 21. Theprocess of claim 16 wherein the alkyl 3-alkoxycarbonylpyrrole-2-acetateis dissolved in an organic solvent prior to being contacted with theacid/alkanol/water mixture.
 22. The process of claim 16 wherein thecontacting is effected by adding the acid/alkanol/water mixture to thealkyl 3-alkoxycarbonylpyrrole-2-acetate.
 23. The process of claim 16wherein the pyrrole monoester is recovered by diluting the reactionmixture with water, extracting the dilute solution with an organicsolvent, and distilling the pyrrole monoester from the solvent.
 24. Theprocess of claim 23 wherein the solvent is methylene chloride.
 25. Theprocess of claim 23 wherein the solvent is toluene.
 26. The processwhich comprises contacting one molar proportion of a3-carboxypyrrole-2-acetic acid corresponding to the formula: ##STR7##with a mixture of about 2-15 molar proportions of a strong mineral acidand amounts of an R₁ OH alkanol and water such as to provide anacid/alkanol mol ratio of about 0.5-6/1 and an acid/water mol ratio ofabout 0.3-10/1 at a temperature of about 40°-100° C., so as to form apyrrole monoester corresponding to the formula: ##STR8## in whichformulas R, R', and R₁ are independently selected from lower alkylgroups.
 27. The process of claim 26 wherein the ingredients of thereaction mixture are employed in amounts such as to provide anacid/3-carboxypyrrole-2-acetic acid mol ratio of about 3.75-10/1, anacid/alkanol mol ratio of about 0.75-2/1, and an acid/water mol ratio ofabout 2-5/1.
 28. The process of claim 26 wherein R and R' are methyl.29. The process of claim 26 wherein the pyrrole monoester is recoveredby diluting the reaction mixture with water, extracting the dilutesolution with an organic solvent, and distilling the pyrrole monoesterfrom the solvent.
 30. The process of claim 29 wherein the solvent istoluene.